Heart disease, especially myocardial infarction, is a leading cause of morbidity and mortality worldwide. Myocardial infarction is an absolute medical emergency whose incidence remains high with 120,000 cases per year in France. According to WHO data, on 50 million annual deaths worldwide, ischemic heart disease are the leading cause of death with 7.2 million deaths from coronary heart diseases. In France, MI prognosis remains poor, (10 to 12% of total annual mortality in adults). In addition, a significant morbidity and socio-economic should be also considered. Following MI, left ventricular remodeling includes early and progressive extracellular matrix degradation, infarct zone expansion, scar thinning, and eventually transition to heart failure (Cohn, et al., 2000; Jugdutt, 2003).
Current antiremodeling therapies are clearly limited, because many ventricles continue to enlarge (Bolognese et al., 2007; Savoye et al., 2006) and morbidity and mortality remain high (Verma et al., 2008). Pharmacological treatments currently available can only delay the progression to end-stage heart failure.
Heart transplantation remains the most effective management of the most severely affected patients, but the shortage of donor organs and complications associated with this intervention limits this approach. Further, lifelong immune suppression often causes serious complications.
Because the dominant cause of heart failure is loss of myocardium as a result of infarction and the limited regeneration potential of cardiomyocytes in mammals, cell therapy may provide a novel therapeutic option to modify left ventricular remodeling processes and prevent post-infarction heart failure. Thus, in recent years, the possibility of using cell transplantation for cardiac repairs has become the focus of intense research. Multiple cell types have been considered for such therapies, including skeletal myoblasts, bone marrow-derived haematopoietic stem cells, mesenchymal stem cells, intrinsic cardiac stem cells (CSCs), embryonic stem cells (ESCs) and induced pluripotent stem (iPS) cells.
Conventional administration techniques use intramyocardial injections of suspended cells in culture medium. However, this technique is plagued by limited cell retention and survival. Several studies showed that more than 80%-90% of grafted cells die within 72 hours after injection into myocardium (Toma et al., Circulation, 105: 93-98, 2002; Maurel et al., Transplantation, 80: 660-665, 2005). Further, it was reported that approximately 90% of the cells delivered through a needle were lost to the circulation or leaked out of the injection site (Leor et al., Circulation, 102: 11156-61, 2000).
In addition, cell-seeded grafts have been proposed for in vitro cardiac tissue growth and subsequent in vivo transplantation. These grafts can consist of embryonic or neonatal cardiomyocytes seeded in three-dimensional scaffolds; the cardiac myocytes cultured in these scaffolds can spatially organize and differentiate into myocardium-like 3-dimensional tissue. These results suggest that cell therapy and tissue engineering of myocardium have potential for myocardial regeneration or replacement. However, current approaches to cardiac regeneration face important challenges. Recipient ischemic tissue may be inadequate for donor cell retention in sufficient quantity to allow for the desired effect, because the survival of cells from any source implanted in the myocardium varies between 1% and 10%. Also, nonspecific delivery of donor cells to other body sites constitutes an unwanted potential side effect.
A particularly useful approach to cardiac regeneration would be a method that could employ injection into the injured area in a manner similar to cell injection therapy (rather than surgical implantation of myocardium-like volume) and that would provide a suitable growth environment for cardiomyocytes.
In recent years, several types of biomaterials, mainly natural proteins, were used in the injectable cardiac tissue engineering, such as fibrin, alginate, matrigel, collagen and chitosan (see for review Wang et al., J. Cell. Mol. Med., 14(5): 1044-1055, 2010).
However, use of natural materials extracted from biological samples is associated with a major risk of microbial transmission, essentially virus transmission. Drawbacks associated with natural materials have prompted the inventors to develop synthetic materials for injectable cardiac tissue engineering.
The inventors had previously developed a silylated hydrogel as a culture matrix for three-dimensional culture of chondrocytes for use for regenerating in vivo cartilaginous tissues (application US 2007/0212389).
However, in view of the great difference between cartilaginous tissue and cardiac tissue, respectively hard and soft tissues, and of the physiological differences between chondrocytes and cardiomyocytes, the latter needing to retain contractile ability to be functional, it was not expected that silylated hydrogel is also usable for culturing functional cardiomyocytes.